The Effects of Chlorhexidine Dressing on Health Care-Associated Infection in Hospitalized Patients: A Meta-Analysis.

Background
To assess the effects of chlorhexidine dressing on health care-associated infection in hospitalized patients.


Methods
We searched for English-language published randomized controlled trials (RCTs) in Cochrane Library, EMBASE and PubMed between January 1998 and January 2018. We used meta-analysis to calculate the risk ratios (RRs) and 95% confidence intervals (CIs) of the data, and using the I 2 assessment to summarize the heterogeneity of RCTs and the funnel plot and Egger regression test to evaluate publication bias.


Results
A total of 13 RCTs were included in our meta-analysis, including 7555 patients and 11,931 catheters. The effects of chlorhexidine dressing on the incidence of catheter-related bloodstream infections (CRBSIs) were reported in 13 RCTs, and the incidence of CRBSIs were 1.3% (80/6160) in the chlorhexidine group and 2.5% (145/5771) in the control group. We used a forest plot to determine the risk ratio (RR) of chlorhexidine dressing on the incidence of CRBSIs, and our results showed that chlorhexidine dressing significantly reduced the incidence of CRBSIs (RR 0.55, 95% CI 0.39-0.77, P<0.001). Moreover, we also analyzed the effects of chlorhexidine dressing on the incidence of catheter colonization and catheter-related infections (CRIs), and our forest plot results showed that chlorhexidine dressing significantly reduced the incidence of catheter colonization (RR 0.52, 95% CI 0.40-0.67, P<0.001) and the incidence of CRIs (RR 0.43, 95% CI 0.28-0.66, P<0.001) in hospitalized patients.


Conclusion
The use of chlorhexidine dressings for hospitalized patients significantly reduce the incidence of CRBSIs, catheter colonization and CRIs.


Introduction
Central venous catheters (CVCs) are an important source of bloodstream infections (BSIs) in hospitalized critically ill patients and are closely related to patients' mortality (1). During the hospitalization, patients complicated with catheterrelated bloodstream infections (CRBSIs) and/or catheter-related infection (CRIs) caused their illness to worsen, the length of hospital stay was extended, and hospitalization expenses increased (2)(3)(4). According to data reported by the Centers for Disease Control and Prevention in US in 2009, the number of CRBSIs in the Intensive Care Unit (ICU) was 12,000-18,000, and the medical expenses generated per case were about $16,550, and the overall mortality rate was increased by 15%-25% (5). At present, due to the limited number of antimicrobial drugs and the emergence of multi-drug resistance, the task of anti-infection is becoming more and more difficult. The Clinical Laboratory Standards Association has developed a standardized method for testing antimicrobial sensitivity, reliability and repeatability (6). The main mechanism of CRBSIs is the in vivo bloodstream contamination caused by the translocation of microorganisms through the skin of the catheter into the blood vessels (7). Therefore, blocking the pathway by which microorganisms invade the blood from the skin is an important method for reducing CRBSIs. Chlorhexidine has a broad spectrum of antibacterial activity against Grampositive bacteria, Gram-negative bacteria, aerobic bacteria, anaerobic bacteria and fungi, and the use of chlorhexidine for skin disinfection in ICU patients reduces the spread of microbes and the incidence of CRBSIs (8). In recent years, there has been increasing interest in using chlorhexidine to disinfect skin to reduce acquired infections in hospitalized patients. Chlorhexidine dressings reduce the incidence of CRBSIs (9)(10)(11)(12)(13), but some studies have the opposite result, do not support the use of chlorhexidine dressings (14)(15)(16)(17)(18). Therefore, in this study, we used a meta-analysis to determine the effects of chlorohexidine dressings on the incidence of CRBSIs, catheter colonization and CRIs in hospitalized patients.

Search Strategy
Under the guidance of librarians, we searched for published studies between January 1998 and January 2018 in three large databases worldwide, including Cochrane Library, EMBASE and Pub-Med. The keywords were used in the search include: "Chlorhexidine", "dressing(s)", "Catheterrelated bloodstream infections", "Catheterrelated Infections", "Central line-associated bloodstream infections" and "catheter colonization". Inclusion criteria: 1.) The selected articles were all published in English; 2.) Randomized controlled trials (RCTs) published before January 2018; 3.) Hospitalized patients used chlorhexidine dressings; 4.) Access to detailed clinical data.

Data Abstraction
We developed a standardized form for extracting all the data, and the two judges independently read the full text of the article and extracted the data. If there was a disagreement between the results or data extracted by the two senators, the third senator presided over the negotiation and discussion to resolve the differences. The data used by our study was limited to published results. The data extracted from each study included: authors of the article, time of publication, study population, department, chlorhexidine group and control group, clinical outcomes, related definitions, etc. The primary outcome was the correlation between chlorhexidine dressing and CRBSIs. The secondary outcome was the effects of chlorhexidine dressing on the incidence of catheter colonization and CRIs.

Risk of Bias Assessment
We used the Cochrane bias risk tool to assess the risk of RCTs bias in each article. According to the methods, two authors independently make high, low or unclear material deviation risk judgments for each RCT (19). We used Review Manager 5.2 to assess the risk of bias in the included studies.

Statistical Analysis
One author entered the obtained data into Review Manager 5.2 software, and another author verifies the accuracy of the input data. We used meta-analysis to calculate the risk ratios (RRs) and 95% confidence intervals (CIs) of the data, and using the I 2 assessment to summarize the heterogeneity of RCTs. When I 2 > 50% or P≥0.10, the heterogeneity was considered significant (20), and we used the random-effects model. If the heterogeneity was not significant, we used a fixed-effects model. We used the Egger regression test and the funnel plot to evaluate publication bias (21). A P value <0.05 was considered statistically significant.

Trial Characteristics
The characteristics of the 13 RCTs were summarized in Table 1, which includes study time, population, department/setting, catheter type, skin disinfection method, chlorhexidine group and control group for each study. Among them, 4 RCTs were for children (9,13,18,23), 2 RCTs were conducted by the same center at different time periods (10,24), and 1 study did not provide a time interval (14). In addition, the relevant definitions and conclusions involved in each of the studies were summarized in Table 2.

Quality Assessment
We used Cochrane bias to assess selection bias or attribution bias in 13 RCTs. As shown in Figs. 2. and 3, because we did not retrieve the blinded evaluation of the study results, the risk of detec-tion and performance bias in most studies was not clear. Three studies showed a high risk of bias due to lack of participants and personnel blinding (11,12,22).

Publication bias
We used a funnel plot and Begg's and Egger's test to assess included RCTs publication bias, and our results showed that the incidence of CRBSIs, catheter colonization and CRIs were no publication biased (P>0.05) (Fig. 7.).

Discussion
Inpatients often need to establish intravascular catheters to treat critically ill and severe diseases such as cancer chemotherapy, parenteral nutrition, hemodialysis, long-term intravenous antibiotics and organ transplantation, etc. (25,26). In the United States, more than 5 million inpatients require central venous access each year (27). However, catheter-related bloodstream infections (CRBSIs) is an important factor leading to increased hospital stay, total cost, and increased mortality (28). The occurrence of CRBSIs is usually caused by skin microbes invading the subcutaneous pipeline, and blocking the displacement of microorganisms can effectively prevent medically relevant CRBSIs (29). Skin disinfection with chlorhexidine significantly reduce the incidence of CRBSIs, which is simple, effective and costeffective (30). A number of studies reported that chlorhexidine dressing can reduce the invasion of extra-catheter microbes and reduce the incidence of CRBSIs (9)(10)(11)(12)(13). However, some studies found that the use of chlorhexidine dressing did not have any effect on the incidence of CRBSIs. In our study, we used a meta-analysis to determine the effects of chlorohexidine dressing on the incidence of CRBSIs, catheter colonization and catheter-related infection (CRIs) in hospitalized patients. A total of 13 RCTs were included in our meta-analysis, including 7555 patients and 11,931 catheters. Our results showed that chlorhexidine dressing significantly reduced the incidence of CRBSIs in hospitalized patients. To determine whether chlorhexidine dressings are equally effective in preventing the incidence of CRBSIs in ICU and non-ICU patients, we performed a subgroup analysis. Our results showed that chlorhexidine dressing significantly reduced the incidence of CRBSIs in both ICU and non-ICU. These results indicated that the use of chlorhexidine dressing significantly reduced the invasion of microbes outside the catheter and inhibited the growth of skin microbes (6)(7)(8).
The six studies included in our meta-analysis first disinfected the skin with chlorhexidine and then covered the catheter inlet with chlorhexidine dressings (14, 16-18, 23, 24), four studies used alcohol for skin disinfection (9)(10)(11)22), and one study did not record the disinfectant used for skin disinfection (15). Moreover, of the 13 RCTs, six RCTs used chlorhexidine-impregnated sponge dressings (10,11,(13)(14)(15)23), and seven RCTs used the chlorhexidine dressings (9, 12, 16-18, 22, 24), which did not indicate the type. A meta-analysis (31), reported that the use of chlorhexidine impregnated dressings can effectively prevent CRBSIs, including arterial catheters for hemodynamic monitoring. In our metaanalysis, eight studies previously evaluated were included (9-11, 14, 15, 22-24), and four RCTs published in recent years were included (12,13,(16)(17)(18), excluding a study that did not retrieve the full text. We also analyzed the relationship between chlorhexidine dressing and the incidence of catheter colonization. Seven RCTs were included in our analysis (9, 10, 13-15, 23, 24), and the incidence of catheter colonization was 5.5% (256/4666) in the chlorhexidine group and 11.8% (531/4514) in the control group. Our results suggested that the use of chlorhexidine dressing significantly reduced the incidence of catheter colonization in hospitalized patients. Moreover, four RCTs reported the effect of chlorhexidine dressings on the incidence of CRIs (10,13,15,24), and our forest plot results showed that chlorhexidine dressing also significantly reduced the incidence of CRIs in hospitalized patients. Our meta-analysis has four limitations. Firstly, the main research object of most of the studies we have included were central venous catheters (CVCs), but one study was peripherally inserted central catheters (PICCs). Different methods of indwelling CVCs might have an impact on the results of the study. Secondly, we only included full-text journal articles published in English, and non-English languages and conference papers were excluded. Therefore, some RCTs were not included in our analysis, which might lead to publication bias or heterogeneity. Thirdly, the products of chlorhexidine dressing used in the studies were different, and the doses of chlorhexidine contained in the dressings were also different.
These factors might have a negative impact on these studies. Fourthly, the effectiveness of chlorhexidine dressings for CRBSI prevention might be inconsistent among different populations, such as neonates, children, adults and seniors. However, our analysis did not separate these populations, so our results might be heterogeneous.

Conclusion
The use of chlorhexidine dressings significantly reduced the incidence of CRBSIs, catheter colonization and CRIs in hospitalized patients. Our results support the use of chlorhexidine dressings in hospitalized patients with indwelling CVCs, which has important implications for CVCs care. Future research should focus on which populations may benefit the most from the use of chlorhexidine dressings, the frequency of chlorhexidine dressing replacement, and the longest indwelling time of CVCs.

Ethical considerations
Ethical issues (Including plagiarism, informed consent, misconduct, data fabrication and/or falsification, double publication and/or submission, redundancy, etc.) have been completely observed by the authors.